1. Field of the Invention
The present invention relates to a pharmaceutical composition, a process of preparing the pharmaceutical composition and a method of using the pharmaceutical composition. Specifically, the invention provides a pharmaceutical composition containing bisphosphonic acids or salts thereof for use in the treatment of osteoporosis and other disorders caused by the abnormal dissolution or deposition of calcium salts.
2. Background of the Invention
Methods of preparing bisphosphonic acids are set forth in U.S. Pat. No. 3,962,432; U.S. Pat. No. 4,054,598; U.S. Pat. No. 4,267,108; U.S. Pat. No. 4,327,039; U.S. Pat. No. 4,407,761; U.S. Pat. No. 4,621,077; U.S. Pat. No. 4,624,947; U.S. Pat. No. 4,746,654; U.S. Pat. No. 4,922,007; and EPO Patent Pub. No. 0,252,504. In particular, methods for the preparation of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid and 4-amino-1-hydroxy-butylidene-1,1-bisphosphonic acid monosodium salt trihydrate may be found in U.S. Pat. No. 4,407,761 and U.S. Pat. No. 4,922,007, respectively.
The pharmaceutical compositions containing the bisphosphonic acids and salts set forth in the patents listed above have the disadvantage that the active ingredients are released from the medications almost instantaneously in the upper gastrointestinal tract causing esophageal discomfort and ulceritis. Thus, the medications have to be taken on arising for the day and at least 30 minutes before the first food, beverage or medication with a full glass (200 ml) of plain water only. The patients are advised to sit upright for about 30 minutes after ingestion of the medication and until their first food of the day. Patients are instructed not to take medication at bedtime or before arising for the day. See Physician's Desk Reference (U.S.) Product Information, 1999, p. 1798.
Several problems have been noted in the preparation of tablet formulations comprising bisphosphonic acid active ingredients, and in particular with enteric coated forms of these active ingredients. For example, U.S. Pat. No. 5,431,920 points out that “standard methods for tablet formulation of bisphosphonic acids suffer from serious difficulties.” Thus, particular dry mix formulations are required when formulating tablets from these active ingredients. In addition, this same patent points out that “[e]nteric coated dosage forms can suffer from stability problems as a result of interactions between the active drug and the acidic enteric coatings.”
The present invention solves these problems by providing dosage forms of bisphosphonic acids that do not require formulation into tablets. The dosage forms of the present invention also have improved stability as compared to prior art formulations.